Mathews suffered an ankle injury when he was tripped in last Sunday's loss to New England. Without Mathews, the Chargers' running game is diminished. Minus a ground attack, the pressure falls on quarterback Philip Rivers against Denver's challenging pass rush.
Rookie Branden Oliver is starting for Mathews.
Also inactive for the Chargers are punter Mike Scifres, wide receiver Dontrelle Inman, defensive tackle Damion Square, tight end Ladarius Green, defensive tackle Ryan Carrethers and outside linebacker Cordarro Law.
Inactive for the Broncos are wide receiver Cody Latimer, running back Ronnie Hillman, cornerback Kayvon Webster, tackle Paul Cornick, tackle Michael Schofield, tight end Jacob Tamme and defensive tackle DT Mitch Unrein.
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